tbuckley/cabot-search huggingface dataset:
CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease
Authors: Ning Zhao, Shalini Chopra, Kai Trepka, Yung-Hua Wang, Sasank Sakhamuri, Nima Hooshdaran, Hyunjung Kim, Jie Zhou, Shion A. Lim, Kevin K. Leung, Emily A. Egusa, Jun Zhu, Li Zhang, Adam Foye, Renuka Sriram, Emily Chan, Youngho Seo, Felix Y. Feng, Eric J. Small, Jonathan Chou, James A. Wells, Rahul Aggarwal, Michael J. Evans
Journal: Clinical Cancer Research (2022)

Abstract Purpose: With the improvement in overall survival with 177Lu-PSMA 617, radioligand therapy (RLT) is now a viable option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, responses are variable, in part due to low PSMA expression in 30% of patients. Herein, we evaluated whether the cell surface protein CUB domain-containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, including in PSMA-low subsets. Experimental Design: CDCP1 levels were evaluated using RNA sequencing from 119 mCRPC biopsies. CDCP1 levels were assessed in 17 post–enzalutamide- or abiraterone-treated mCRPC biopsies, 12 patient-derived xenografts (PDX), and prostate cancer cell lines. 4A06, a recombinant human antibody that targets the CDCP1 ectodomain, was labeled with Zr-89 or Lu-177 and tested in tumor-bearing mice. Results: CDCP1 expression was observed in 90% of mCRPC biopsies, including small-cell neuroendocrine (SCNC) and adenocarcinomas with low FOLH1 (PSMA) levels. Fifteen of 17 evaluable mCRPC biopsies (85%) demonstrated membranous CDCP1 expression, and 4 of 17 (23%) had higher CDCP1 H-scores compared with PSMA. CDCP1 was expressed in 10 of 12 PDX samples. Bmax values of approximately 22,000, 6,200, and 2,800 fmol/mg were calculated for PC3, DU145, and C4–2B human prostate cancer cells, respectively. 89Zr-4A06 PET detected six human prostate cancer xenografts, including PSMA-low tumors. 177Lu-4A06 significantly suppressed growth of DU145 and C4–2B xenografts. Conclusions: The data provide the first evidence supporting CDCP1-directed RLT to treat mCRPC. Expanded studies are warranted to determine whether CDCP1 is a viable drug target for patients with mCPRC.
Use of a Real-Time Locating System to Assess Internal Medicine Resident Location and Movement in the Hospital
Authors: Michael A. Rosen, Amanda K. Bertram, Monica Tung, Sanjay V. Desai, Brian T. Garibaldi
Journal: JAMA Network Open (2022)

<h3>Importance</h3> The patient-physician clinical encounter is the cornerstone of medical training, yet residents spend as little as 12% of their time in direct patient contact. <h3>Objectives</h3> To use a real-time locating system (RTLS) to characterize intern work experiences in the hospital, understand factors associated with time spent at patients' bedsides, and inform future interventions to increase time spent with patients. <h3>Design, Setting, and Participants</h3> This cross-sectional study was conducted from July 1, 2018, to June 30, 2019 (ie, the academic year 2018-2019). Internal medicine residents from postgraduate year 1 (interns) at an academic medical center wore an infrared badge that recorded location and duration (eg, patient room, ward hall, physician workroom). Data were analyzed from September 1, 2020, to August 30, 2021. <h3>Main Outcomes and Measures</h3> Main outcome was time (in minutes) at the bedside; the unit of analysis was a 24-hour intern day or interval of time within the day (eg, rounding period). Descriptive statistics are reported overall, by intern, and for 5 clinical service categories. Multilevel modeling assessed the association of intern, service, and calendar time with time spent at the bedside. <h3>Results</h3> Data from 43 of 52 interns (82.7%) encompassing 95 275 hours of observations were included for analyses. Twenty-six interns (60.5%) were women. Interns were detected for a mean (SD) of 722.8 (194.4) minutes per 24-hour period; 13.4% of this time was spent in patient rooms (mean [SD] time, 96.8 [57.2] minutes) and 33.3% in physician workrooms (mean [SD] time, 240.9 [228.8] minutes). Mean percentage of time at the bedside during a 24-hour period varied among interns from 8.8% to 18.3%. Mean (SD) percentage of time at the bedside varied by service for the 24-hour period from 11.7% (6.6%) for nononcology subspecialties to 15.4% (6.0%) for oncology, and during rounds from 8.0% (12.4%) for nononcology subspecialties to 26.5% (12.1%) for oncology. In multilevel modeling, the individual intern accounted for 8.1% of overall variance in time spent at the bedside during a 24-hour period, and service accounted for 18.0% of variance during rounds. <h3>Conclusions and Relevance</h3> The findings of this cross-sectional study support previous evidence suggesting that interns spend only a small proportion of time with hospitalized patients. The differences in time spent in patients' rooms among interns and during rounds constitute an opportunity to design interventions that bring trainees back to the bedside.
Abstract 855: Analysis of canonical uveal melanoma mutations reveals novel signaling effects
Authors: Dawn Alexandra Owens, Stefan Kurtenbach, Jeffim N. Kuznetsoff, Daniel A. Rodriguez, Anthony Cruz, J. Harbour
Journal: Cancer Research (2022)

Abstract Uveal Melanoma (UM) is the most common primary ocular cancer in adults. Virtually all UM have activating mutations in the Gq signaling pathway. Metastatic risk in patients correlates with additional secondary mutations, where the lowest metastatic risk (class 1) is associated with EIF1AX and SF3B1, and the highest metastatic risk (class 2) is associated with BAP1 mutations. The interplay between the initiating Gq pathway mutations, and the secondary mutations found in all UM has not been well understood yet. Here, we utilize a multi-omics approach, to describe gene expression changes, the proteome, and phosphatome, following GNAQ mutation and BAP1 knockout in primary human uveal melanocytes. We generated human uveal melanocyte cell lines with inducible and specific mutations and analyzed via RNAseq, ATACseq, and mass spectrometry. Results reveal significant changes in pathways related to p53, chromatin regulation/modification, gene expression, and RNA processing with noted dysregulation of genes JUN, HDAC4, YAP, and SOX10, which cause senescence in melanocytes following GNAQ mutation, and are relieved through additional mutation in BAP1. Citation Format: Dawn Alexandra Owens, Stefan Kurtenbach, Jeffim N. Kuznetsoff, Daniel A. Rodriguez, Anthony Cruz, J. Harbour. Analysis of canonical uveal melanoma mutations reveals novel signaling effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 855.
Abstract 3656: Breast cancer care quality in Peru
Authors: Andrea Anampa-Guzman, Rushmely Gaby Perez-Mendez, Juan Huaccho-Rojas, Martha Villar-Lopez, Elsy Mini-Diaz
Journal: Cancer Research (2022)

Abstract Although many studies indicate that the use of complementary medicine by cancer patients is common and widespread, few studies focused on patients' quality of care using complementary therapies. The overall health care quality perception of patients in Lima, the capital of Peru, was reported to be 68.9% according to the SERVQUAL questionnaire, which grades as acceptable. Breast cancer is the most common cancer in Peru. This study aims to determine the perception of health care quality for breast cancer patients in Lima. This is a cross-sectional study. The perspectives of 182 breast cancer patients about the quality of care at the largest hospital in Lima were assessed. One hundred seventeen patients (64.29%) were only seen at the Oncology Department, and 65 patients (35.71%) were seen at both the Oncology Department and Complementary Medicine Department. The quality perception is based on five dimensions: Reliability, responsiveness, assurance, empathy, and tangibility. The percentage has to be 60 to be an acceptable level. The average age was 58.81 years. The overall and oncology-only groups quality perceptions were not acceptable, 57.32%, and 53.65%, respectively. The oncology and the complementary patient group reported adequate general perception (63.92%). Perception of empathy and assurance were at acceptable levels for both groups. Reliability and tangibility did not receive a satisfactory grade in any group. The responsiveness level was only adequate in the complimentary and oncology group. The breast cancer patients’ perception of the health care quality who received Complementary Medicine services was significantly higher than the oncology-only group. We did not find a significant difference between the dimensions of quality and educational level, type of insurance, and the professional who attended the patient. In conclusion, the patients who were seen at the oncology and complementary medicine reported a better perception of the quality of healthcare. More studies are needed to improve healthcare in breast cancer patients. Citation Format: Andrea Anampa-Guzman, Rushmely Gaby Perez-Mendez, Juan Huaccho-Rojas, Martha Villar-Lopez, Elsy Mini-Diaz. Breast cancer care quality in Peru [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3656.
Abstract 119: Pan-cancer analysis of HIF pathways defines a robust molecular signature that reflects tissue and cellular hypoxia in bulk and single-cell RNA-seq analyses
Authors: Olivia Lombardi, Ran Li, Silvia Halim, Peter J. Ratcliffe, David R. Mole
Journal: Cancer Research (2022)

Abstract Low levels of tissue oxygen, or intra-tumor hypoxia, is a common feature of many solid cancers in which dysregulated cell proliferation often outstrips the ability to develop new functional blood vessels. Furthermore, hypoxia pathways may also be activated in response to mutation in key tumor suppressor genes or oncogenes. Importantly, in many types of cancer, activation of hypoxia pathways is associated with a clinically aggressive phenotype as well as with resistance to therapy. Indeed, hypoxia drives many of the “hallmarks” of cancer, including cell proliferation, apoptosis, metabolism, immune responses, genomic instability, vascularization, invasion and metastasis. However, the full-range of genes activated by hypoxia varies greatly between cell-types and for many this remains uncharacterized. The key mediator of the cellular transcriptional response to hypoxia is the HIF (hypoxia-inducible factor) family of transcription factors. Here, we generate pan-genomic datasets encompassing HIF ChIP-seq and RNA-seq across cancer cell lines from diverse common tumor types. We then employ integrated analysis of our 72 transcriptome and whole-genome-binding datasets to define a core set of HIF-target genes that are conserved across multiple cell types. We show that these genes can be used to identify HIF activation and tumor hypoxia in bulk RNA-seq analysis of solid tumors, and that this can be applied to large tumor databases (TCGA). We then leverage this analysis to identify tumor-type-specific HIF-associated genes in 32 different cancer types, including those lacking cell-culture models. We further show that these conserved HIF-target genes can be applied to single cell RNA-seq datasets from solid tumors and used to examine intra-tumor heterogeneity in HIF-pathway activation within individual cancer samples. Importantly, using a panel of genes reduces the phenomenon of “drop-out” typically observed in gene-level expression in these datasets. Lastly, applying this gene signature to single cell data allows the hypoxia response to be deconvoluted across diverse cell-types in heterogenous tumor samples. This includes not only the identification of HIF-activity in cancer cells, but also in non-cancer cells within the tumor, thereby allowing the effects of intra-tumor hypoxia on stromal responses (such as tumor angiogenesis) to be studied in vivo in solid tumors. Citation Format: Olivia Lombardi, Ran Li, Silvia Halim, Peter J. Ratcliffe, David R. Mole. Pan-cancer analysis of HIF pathways defines a robust molecular signature that reflects tissue and cellular hypoxia in bulk and single-cell RNA-seq analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 119.
Abstract 2943: Acoustic cell separation platform for efficient preparation of single cell/nuclei suspension from complex samples for genomics analysis
Authors: Liping Yu
Journal: Cancer Research (2022)

Abstract Preparing a single cell suspension is a critical step in any solid tissue for genomics analysis as the presence of cellular debris, dead cells and free RNA will cause incorrect cell count, noise in sequencing read and possibly clogging of the microfluidic chip. Single cell preparation not only involves the tissue dissociation process but the “clean-up” step of the dissociation product. Current methods for removing dead cells and debris use magnetic beads and density gradient centrifugation, which are lengthy and costly, and often result in low cell recovery. Here we present a high-speed acoustic cell separation platform—MARS® Sample Preparation system. The system has three independent modules and each has an acoustic cell processing chip (CPC) which creates different moving trajectory of live cells, dead cells, and cellular debris in the acoustic field to achieve high efficiency of single cell separation. MARS® sample preparation provides fast, gentle, and label-free protocol to separate single cells and single nuclei from various types of organs and dissociation processes including manual enzymatic approach and automatic platform. Separated single cells and nuclei demonstrate compatibility with the downstream single cell genomics platform. We here report the separation of live single cells and nuclei from mouse brain tissue dissociation with over 99% removal of myelin and other debris, and 60%-80% recovery of cells and nuclei. Those results were obtained on the MARS® with 0.8mL/min flow rate and three samples in parallel process. Samples before and after MARS® acoustic process were analyzed with both flow cytometry and imaging-based cell counter. The performance of “clean-up” of the acoustic process was compared to conventional Percoll based centrifugation method and showed significant advantage. The results of separating kidney cells/nuclei, lung cells/nuclei, as well as spleen cells also demonstrated high debris removal and cell recovery over several samples processed in multiple batches. MARS® sample preparation platform and its acoustic technology provide a powerful new tool for single cell preparation for expanded application of single cell genomics. Citation Format: Liping Yu. Acoustic cell separation platform for efficient preparation of single cell/nuclei suspension from complex samples for genomics analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2943.
Abstract 2741: A communication theory framework for modeling cytokine-mediated signaling in healthy and breast cancer derived peripheral blood immune cells
Authors: Adina Matache, Aleksandra Karolak, Sergio Branciamore, Andrei Rodin, Peter P. Lee, Russell C. Rockne
Journal: Cancer Research (2022)

Abstract Previous studies have shown that approximately 40% of estrogen receptor positive (ER+) breast cancer (BC) patients harbor immune signaling defects in their blood at diagnosis that predicts overall survival. The aim of this work is to apply communication theory and signal processing methods to model cytokine-mediated signaling errors in immune cells in the peripheral blood. Our approach uses communication theory concepts to develop a communication system model consisting of a transmitter, receiver, and channel, applied to the JAK/STAT signaling pathway and tested using multi-color flow cytometry analysis of peripheral blood mononuclear cells stimulated with IFNγ, IL-2, IL-6, IL-4, IL-10, IL-12, or TGFβ in samples from 2 BC patients and 4 healthy controls. We use our model to estimate the detection error rate when one of the 7 cytokines is being transduced through the JAK/STAT signaling pathway, but its signal is being received on multiple phosphorylated signal transducers and activators of transcription (pSTAT) molecules. In addition, we extend the measured error rate value to an error rate curve by varying the signal-to-noise ratio available to the receiver in our system model. Our results show a trend towards higher detection error rates in immune cells from BC patients as compared to healthy controls, which may indicate altered immune signaling and incorrect cell decisions in these patients. Also, considering different cell subtypes, our results show two orders of magnitude increase in error rate in CD4+ memory T cells compared to CD4+ naïve T cells in BC patients. With further development, we believe that our communication theory model and quantification of optimal signal detection in cells will provide a better understanding into how immune cells can accurately “decode” information to respond properly to various signals and how the immune signaling is altered in BC patients, causing better or worse outcomes. The benefit of our novel approach is that it integrates all the transmitted (cytokines) and received signals (pSTATs) into a single communications framework that can be efficiently analyzed together. Citation Format: Adina Matache, Aleksandra Karolak, Sergio Branciamore, Andrei Rodin, Peter P. Lee, Russell C. Rockne. A communication theory framework for modeling cytokine-mediated signaling in healthy and breast cancer derived peripheral blood immune cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2741.
Abstract 1049: Modulating the polymorphic UGT1A1 gene to enhance camptothecin anti-colorectal effect
Authors: Dalia Al Saeedy, Reham K. Abuhijjleh, Ahmed Gouda, Sherif F. El-Khamisy, Ahmed M. Al-Abd
Journal: Cancer Research (2022)

Abstract Several semisynthetic analogs of camptothecin (CPT) are used clinically for the treatment of various types of cancers, including colorectal (CRC) cancer, despite their severe, potentially life-threatening toxicities. Studies defined key mutations in the UDP-glycosyltransferase 1 polypeptide A1 (UGT1A1) gene in CRC which play a role in the toxicity and resistance of a broad class of anti-cancer drugs that target DNA topoisomerases. UGT-1A1 is responsible for the glucuronidation and detoxification of the active/toxic metabolite of the topoisomerase I poison, CPT and its analogues, SN-38. Herein, we investigated the potential chemomodulatory effects of a UGT1A1-gene inducer, phenytoin, to the anticancer properties of CPT. The cytotoxic effects of CPT, phenytoin and their combination were evaluated against various colorectal cancer cell lines (SW620, HT29 and HCT116) using sulforhodamine-B assay under normoxic and hypoxic conditions. In HT29, CPT alone and after combination treatment had IC50’s of 0.1235 µM and 0.0269 µM, respectively, under normoxic conditions; and 0.1352 µM and 0.0476 µM, respectively, under hypoxic conditions. In SW620, CPT alone and after combination treatment had IC50’s of 1.9861 µM and 0.0087 µM, respectively, under normoxic conditions; and 1.9549 µM and 0.0024 µM, respectively, under hypoxic conditions. In HCT116, CPT alone and after combination treatment had IC50’s of 0.163 µM and 0.0157 µM, respectively, under normoxic conditions; and 0.1013 µM and 0.0766 µM, respectively, under hypoxic conditions. Flow cytometric analysis after annexin-V/FITC staining showed that the combination treatment significantly induced total apoptosis in all cell lines under investigation. In both HT29 and SW620, the combination treatment significantly suppressed the autophagy compared to CPT treatment alone using acridine orange staining coupled with flowcytometry. Cell cycle analysis using DNA content flowcytometry after PI staining showed significant S-phase arrest in the combination treatment when compared to the control across all cell lines under investigation. This indicates that sub-molecular mechanisms of phenytoin induced chemomodulatory effect to CPT anticancer properties is oxygen tension dependent. Further investigation for the intratumoral metabolism of CPT under hypoxic as well as normoxic conditions and particularly those attributed to UGT-1A1 is currently undergoing. Citation Format: Dalia Al Saeedy, Reham K. Abuhijjleh, Ahmed Gouda, Sherif F. El-Khamisy, Ahmed M. Al-Abd. Modulating the polymorphic UGT1A1 gene to enhance camptothecin anti-colorectal effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1049.
Abstract 3599: Helical stapled peptides derived from DIRAS3 block KRAS dimerization and downstream MEK/ERK signaling in pancreatic and ovarian carcinomas
Authors: Joshua P. Gray, Gamze E. Bildik, Margie N. Sutton, Yong Zhou, Steven Millward, John F. Hancock, Zhen Lu, Robert C. Bast
Journal: Cancer Research (2022)

Abstract The overall 5-year survival for pancreatic ductal adenocarcinoma (PDAC) has changed little over the past few decades, and PDAC is predicted to become the second leading cause of cancer-related mortality in the next decade in Western countries. Low grade serous ovarian cancer (LGSOC) is a slow-growing but generally chemo-resistant cancer with few effective treatments for recurrent disease. More than 90% of PDAC and up to 40% of LGSOC express mutationally activated KRAS that drives persistent cell division, anti-apoptosis, cell migration and metastasis. Preventing signaling from the KRAS oncoprotein has been challenging. While recent studies have shown promising results by targeting the binding pocket in Switch II for development of KRAS mutant-specific inhibitors for the G12C mutant and G12D mutant, targeting other mutations remains a work in progress. We have discovered that DIRAS3, a novel endogenous physiological RAS inhibitor, blocks KRAS activity by directly binding KRAS with high affinity, inhibiting KRAS dimerization/nanoclustering and blocking effector activation. In this study we have developed drug-like, helical 10-mer stapled peptides derived from DIRAS3 α5 domain. Preliminary studies show that these lead compounds associate with KRAS with low nanomolar affinity, are largely resistant to serum proteases, and rapidly cross the cellular membrane. Functionally, DIRAS3 peptides—but not control peptides—block KRAS homodimers in ReBiL split luciferase assays of KRAS dimerization and disrupt nanoclustering by TEM analysis of GFP-KRAS(G12V)-labeled gold nanoparticles on the inner leaflet of the plasma membrane of cells. Moreover, DIRAS3 peptides significantly inhibit phospho-ERK, decrease cell viability and induce apoptosis in pancreatic and low-grade ovarian cancer cells with KRAS mutations. Finally, daily treatment with stapled DIRAS3-derived peptides inhibited growth of ASPC-1 (KRAS G12D) PDAC xenografts and improved survival. Thus, our study suggests that development of DIRAS3 stapled peptides may provide a novel therapeutic approach to target mutant KRAS-driven cancers. Citation Format: Joshua P. Gray, Gamze E. Bildik, Margie N. Sutton, Yong Zhou, Steven Millward, John F. Hancock, Zhen Lu, Robert C. Bast. Helical stapled peptides derived from DIRAS3 block KRAS dimerization and downstream MEK/ERK signaling in pancreatic and ovarian carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3599.